A role for oxidative stress in the pathogenesis of AMD is strongly supported by the recent AREDS data showing that supplemental antioxidants and zinc can significantly reduce the risk of disease progression. The goal of this renewal application is to define genetic and biochemical markers of retinal oxidative stress so that people at higher risk or at earlier stages of AMD can be identified and treated with supplementation of their antioxidant defense before the development of significant vision loss. Our AREDS ancillary study showed that plasma thiol/disulfide redox state became oxidized with time in AMD patients without antioxidant supplementation, but not in those with antioxidants. In addition, we found that oxidation of plasma cysteine and glutathione pools are associated with risk factors of AMD, such as aging and smoking. Our preliminary data indicate that plasma pro-apoptotic and pro-inflammatory cytokines, such as soluble Fas ligand, are correlated with plasma redox status and AMD. Furthermore, recent results, performed with new collaborators at Vanderbilt, indicate that specific mitochondrial DNA haplotypes may be associated with an increased risk of AMD. Taken together, the data strongly suggest that the etiology and progression of AMD involves genetic/environmental interaction, and oxidative stress is a common mechanism contributing to age-related tissue degeneration, inflammation and mechanisms of genetic predisposition. Our central hypothesis for this application is that genetic and plasma biochemical markers of oxidative stress can be used to identify people with increased risk of AMD and to predict the outcome of clinical treatment with antioxidant supplementation. We propose three specific aims to answer the following questions. (1) Are plasma markers of oxidative stress and proinflammatory cytokines associated with aging and AMD? (2) Are there specific mitochondrial DNA polymorphisms that are associated with markers of increased oxidative stress as well as the AMD phenotype? (3) Can dietary interventions modify plasma markers of oxidative stress and proinflammatory cytokines in AMD patients with different genetic backgrounds. Results from this comprehensive project of basic mechanistic, translational and clinical studies will facilitate the early diagnosis and treatment of AMD and directly suggest new therapeutic strategies that focus on strengthening the antioxidant capacity of the retina and the RPE.